Pathological aggression has a devastating socio-economic impact, and is a leading mortality in young male Americans. The development of preventative and therapeutic tools for the management of this disorder is greatly limited by our partial understanding of its pathophysiology. The objective of this exploratory R21 proposal is to understand the mechanisms of interaction between the three best-characterized vulnerability factors for pathological aggression: early psychosocial stress;low activity of brain monoamine oxidase (MAO) A, the major enzyme for the degradation of brain serotonin (5-HT), norepinephrine (NE) and dopamine (DA);male gender, in relation to the high levels of androgen testosterone and its metabolites. In fact, recent data show that the high risk to develop post-pubertal aggression in maltreated boys is mainly observed in carriers of genetic variants associated with low MAO A activity. We found that 5-1 reductase (5AR), the enzyme that converts testosterone into its potent androgenic metabolite dihydrotestosterone (DHT), is affected by early stress and MAO-A deficiency;furthermore, its inhibition by finasteride reduces the high aggression of patients and MAO A knockout mice. The leading hypothesis of this proposal is that the interaction of low MAO A activity and early psychosocial stress results in long-term changes in monoamine levels and steroidogenic pathways in the brain. In males, the increase in testosterone levels at puberty interacts with these changes, resulting in imbalances in steroids and monoamines in prefrontal cortex and other key brain regions for emotional regulation. These neurochemical perturbations lead to aggression and antisocial behavior. We will address this hypothesis using male WT, MAO A KO mice and a newly-developed line of MAO A hypomorphic (MAO Aneo) mice, with very low brain MAO A activity. These mice show lower levels of aggression than MAO A KO mice and are an excellent model for carriers of low MAO A- activity genetic variants. In Aim 1, we will study the effects of the interaction between MAO-A genetic variants and early stress in the developmental trajectory of aggression in male mice. To this end, we will subject male MAO Aneo and KO pups (and their WT littermates) to maternal separation (a highly isomorphic model of child neglect) for the first three weeks of postnatal life;aggression-related behaviors before, during and after puberty will be correlated with the levels of MAO A and 5AR, as well as 5-HT, NE, DA, testosterone and their metabolites in key brain regions for the regulation of aggression. In Aim 2, we will study the role of testosterone and 5AR in the aggression of MAO A-deficient mice, by assessing the behavioral and molecular changes induced by castration and finasteride treatment. The proposed project will help establish the neurobiological bases of pathological aggression. The translational application of these findings will be critical to define new biomarkers, endophenotypes and molecular targets for early prevention, diagnosis and treatment of this disorder. PUBLIC HEALTH RELEVANCE: This application proposes to use a highly innovative approach to identify the mechanisms of interactions between the three best-characterized vulnerability factors for pathological aggression: early psychosocial stress, low activity of monoamine oxidase and male gender (in relation to testosterone and its metabolism). This knowledge will help establish the neurobiological bases of pathological aggression, which will be translated into novel biomarkers, endophenotypes and molecular targets for early prevention, diagnosis and treatment of this disorder.